Project Summary The Early Phase Clinical Cancer Prevention Consortium proposes to develop, implement, and complete early clinical trials targeting cellular stemness. Most cancers display a hierarchical organization that is driven by a population of cells that are ?stem-like?. Inflammatory stress drives increased stem cell self-renewal across different organ sites. The sources of chronic inflammatory stess include obesity, explosures (alcohol, chemicals), infectious agents, microbial dysbiosis, and genetic polymorphisms. Of these, the obesity-associated metabolic syndrome associated is reaching epidemic proportions. This consortium addresses the overarching hypothesis that inflammatory-induced shifts in the tissue stromal environment increase stem cell self-renewal and enhance epithelial mesenchymal transformation. These shifts can be reversed or dampened by biomarker driven dosing of clinical preventive agents, either alone or in combination. We select agents that target the adverse metabolic milieu resulting from inflammatory exposures and driving stem cell proliferation. The Consortium proposes the following aims: 1. To develop and submit at least three proposals each year for early phase trials for the prevention of obesity-related cancers (colon, lower esophagus, breast, prostate, bladder); 2. To conduct 1 to 3 early phase cancer prevention trials per year within the fiscal capacity of the grant that include evaluating translational endpoints in biospecimens, asssessing the pharmacokinetics and pharmacodynamics, and obtaining mechanistic proof-of-principle data; and 3. To manage all aspects of study operations while complying with all applicable rules and regulations for the conduct of clinical trials. The University of Michigan Rogel Cancer Center is the lead organization of a consortium consisting of 9 institutions of which all are within NCI Core Funded Cancer Centers. The intellectual diversity and strong academic accomplishement of our consortium permits deep intellectual engagement combined with the experienced logistics of participant recruitment and retention, and the infrastructure support available in NCI supported cancer centers. We have established processes to ensure rapid turn-around of letters of intent and protocol documents, uniform sample handling, management and shipment, and rapid analysis of biosamples. The Consortium will collaborate with other the CP-CTNet consortia to create synergies of science and resources, enabling paradigm shifts that rapidly test and prioritize agents for Phase III trials conducted in individuals at increased risk of cancer.